Phase I-II Study to Determine the Maximum Tolerated Dose (MTD) of AUY922 in Advanced Solid Malignancies, and Efficacy in HER2+ or ER+ Locally Advanced or Metastatic Breast Cancer Patients

Inclusion criteria

• Dose-escalation and MTD dose expansion arm: Patients with histologically confirmed, advanced malignant solid tumors whose disease has progressed on standard therapy or for whom no standard therapy exists.

Breast cancer phase II expansion arms only:

• Females patients with HER2 positive non-operable locally advanced or metastatic breast cancer must have:

• History of trastuzumab resistance, defined as either local or systemic disease progression on treatment with at least 8 weeks of a trastuzumab containing regimen.
• Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or lapatinib in combination with other agents) for metastatic disease
• Patients who develop metastases while receiving adjuvant or neo-adjuvant trastuzumab are eligible.

HER2 positive patients, tumor/s must demonstrate HER2 over-expression based on either:

• Immunohistochemistry (IHC) at the 3+ level, or
• IHC 2+ confirmed by fluorescence in-situ hybridization (FISH). Tumors tested by FISH must be positive by the specific FISH assay for the amplification of HER2.
• Female patients with ER positive non-operable locally advanced or metastatic breast cancer patients who received standard sequence lines of endocrine therapy and whose disease has progressed on at least one and up to 3 lines of endocrine and/or cytotoxic therapy for advanced disease.
• All patients must have at least one measurable lesion as defined by RECIST. Irradiated lesions are only evaluable for disease progression.
• All patients must have progressive disease before entering the study
• Age ≥ 18 years.
• World Health Organization (WHO) Performance Status of ≤ 2.
• Life expectancy of ≥ 12 weeks.
• Absolute Neutrophil Count (ANC) 1.5 x 109/L; hemoglobin (Hgb) 9 g/dl; platelets (plt) 100 x 109/L; potassium, calcium, magnesium and phosphorus within normal limits or correctable with supplements; AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present; serum bilirubin 1.5 x ULN; serum albumin > 2.5g/dl and serum creatinine 1.5 x ULN or 24-hour clearance 50 ml/min

Exclusion criteria

• Patients with CNS metastasis which are:

• Symptomatic or
• Require treatment for symptom control and/or
• Growing

Note: patients without clinical signs or symptoms of CNS involvement are not required to have a CT/MRI of the brain

• Prior treatment with any HSP90 or HDAC inhibitor compound.
• Patient who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:

• Chemotherapy within 4 weeks
• Radiotherapy within 4 weeks
• Palliative radiotherapy: within 2 weeks
• Trastuzumab treatment within 4 weeks
• Nitrosoureas, mitomycin and monoclonal antibodies (except trastuzumab): within 6 weeks
• Any continuous-dosing (i.e. daily dosing, every-other-day dosing, Monday- Wednesday-Friday dosing, weekly etc) of systemic anticancer treatment for which the recovery period is not known, or investigational drugs (i.e. targeted agents) within a duration of ≤ 5 half lives of the agent and their active metabolites (if any)
• Patients who have not recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose.
• Pregnant or lactating women.
• Cardia exclusion criteria:

• History (or family history) of long QT syndrome.
• Mean QTc ≥ 450 msec on screening ECG
• History of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start.
• History of heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO
• Known diagnosis of HIV infection (HIV testing is not mandatory).
• Acute or chronic liver disease, acute or chronic renal disease or other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
• Cardiac exclusion criteria:

Mean QTc ≥ 450 msec on screening ECG and clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II) or 3rd degree AV block; clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions > 1mm, or 2nd (Mobitz II) or 3rd degree AV block.

History (or family history) of long QT syndrome, heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO, history of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start; history or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes.

Other protocol-defined inclusion/exclusion criteria may apply